Stent And Delivery System With Reduced Chemical Degradation

ABSTRACT

Stents and delivery systems with reduced chemical degradation and methods of sterilizing the same are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. application Ser.No. 11/804,234, filed on May 16, 2007, which is incorporated byreference as if fully set forth, including any figures, herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a reducing chemical degradation to medicalarticles due to sterilization.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a retractable sheath or a sock. Whenthe stent is in a desired bodily location, the sheath may be withdrawnwhich allows the stent to self-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as, hoop or circumferential strengthand rigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. Generally, it is desirable to minimize recoil.

In addition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Longitudinal flexibility isimportant to allow the stent to be maneuvered through a tortuousvascular path and to enable it to conform to a deployment site that maynot be linear or may be subject to flexure. Finally, the stent must bebiocompatible so as not to trigger any adverse vascular responses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.

A stent and delivery system typically undergo sterilization to reducetheir bioburden to an acceptable sterility assurance level (SAL). Thereare numerous methods of sterilizing medical devices, the most commonbeing ethylene oxide treatment and treatment with ionization radiationsuch as electron beam and gamma radiation. Generally, it is desirablefor the sterilization procedure to have little or no adverse affects onthe performance of a sterilized article.

SUMMARY

Various embodiments of the present invention include a stent comprising:a substrate; a coating comprising a polymer over the substrate; and achemical degradation-reducing substance that reduces or prevent chemicaldegradation in a polymeric portion of the stent, the chemicaldegradation arising from exposure to radiation during sterilization.

Additional embodiments of the present invention include a stent deliveryassembly comprising a polymeric portion of the assembly, the polymericportion including a chemical degradation-reducing substance that reducesor prevents chemical degradation in the polymeric portion arising fromexposure to radiation during sterilization.

Further embodiments of the present invention include a method ofsterilizing a stent delivery assembly, the method comprising exposing astent delivery assembly to radiation to reduce the bioburden of theassembly, wherein a polymeric portion of the assembly includes asubstance that reduces or prevents chemical degradation in the polymericportion arising from the exposure to the e-beam radiation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIG. 2 depicts a stent mounted on a stent delivery assembly.

FIG. 3 depicts a schematic illustration of a fixture that supports apackage containing a stent disposed on a stent-delivery assembly.

FIG. 4 depicts a close-up schematic view of a stent surface showing astent substrate with a coating.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention relate to reducing orpreventing chemical degradation to polymeric-containing portions ofstents and stent delivery assemblies due to radiation sterilization.Embodiments also include reducing or preventing chemical degradation todrugs or active agents on stents.

The embodiments described herein may be may be applied generally toimplantable medical devices and delivery systems for implantable medicaldevices. The embodiments are particularly relevant, for reasonsdiscussed below, to implantable medical devices, such as a stents,having a polymeric substrate, a polymer-based coating, a drug-deliverycoating, or a combination thereof. A polymer-based coating may contain,for example, an active agent or drug for local administration at adiseased site. An implantable medical device may include a polymer ornon-polymer substrate such as metal with a polymer-based coating.

Examples of implantable medical devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Abbott Cardiovascular Systems Inc., Santa Clara, Calif.). Theunderlying structure or substrate of the device can be of virtually anydesign.

The embodiments herein are also generally applicable to a deliverysystems or assemblies used to implant an implantable medical device. Theembodiments are particularly relevant, to stent delivery systems fordelivering stents at a treatment site. Various sections of stentdelivery systems, such as the catheter, stent delivery balloon, andrestraining sheath, can be composed in whole or in part of polymers.Such sections can also be composed of composite metal polymer material.Representative materials that can be used to form sections of a stentdelivery assembly include, but are not limited to, polyetheretherketones(PEEK), polypropylene, low density polyethylene, high densitypolyethylene, ethylene vinyl acetate, nylon, polyesters, polyethyleneterephthalate, Surlyn™, Pebax®, and polyurethanes.

FIG. 1 depicts a view of a stent 10. In some embodiments, a stent mayinclude a pattern or network of interconnecting structural elements 15.Stent 10 may be formed from a tube (not shown). The pattern ofstructural elements 15 can take on a variety of patterns. The structuralpattern of the device can be of virtually any design. The embodimentsdisclosed herein are not limited to stents or to the stent patternillustrated in FIG. 1. The embodiments are easily applicable to otherpatterns and other devices. The variations in the structure of patternsare virtually unlimited. A stent such as stent 10 may be fabricated froma tube by forming a pattern with a technique such as laser cutting orchemical etching.

A stent such as stent 10 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form a tube. A stent patternmay be formed on a polymeric tube by laser cutting a pattern on thetube. Representative examples of lasers that may be used include, butare not limited to, excimer, carbon dioxide, and YAG. In otherembodiments, chemical etching may be used to form a pattern on a tube.

FIG. 2 depicts stent 10 mounted on a stent delivery assembly 100 whichis used to deliver the stent and implant it in an artery 124, peripheralartery, or other vessel or lumen within the body. Stent deliveryassembly 100 shown in FIG. 2 includes a catheter 103 which has aproximal end 115 and a distal end 117. The stent delivery assembly isconfigured to advance through the patient's vascular system by advancingover a guide wire by any of the well known methods.

Stent delivery assembly 100 as depicted in FIG. 2 includes a port 120where a guide wire 118 will exit the catheter. The distal end of theguide wire exits catheter distal end 119 so that the catheter advancesalong the guide wire on a section of the catheter between the port 120and the catheter distal end. Stent 10 is mounted on an expandable member122 (balloon) and is crimped tightly thereon so that stent 100 andexpandable member 122 present a low profile diameter for deliverythrough the coronary arteries.

In a typical procedure to implant stent 100, guide wire 118 is advancedthrough the patient's vascular system by well known methods so that thedistal end of the guide wire is advanced past a diseased area 126.Thereafter, stent delivery assembly 100 is advanced over the guide wireso that the stent assembly is positioned in the target area. Expandablemember or balloon 122 is inflated by well known means so that it expandsradially outwardly and in turn expands the stent radially outwardlyuntil the stent is apposed to the vessel wall. The expandable member isthen deflated and the catheter withdrawn from the patient's vascularsystem.

Sterilization is typically performed on medical devices, such as stentsand delivery systems, to reduce the bioburden. Bioburden refersgenerally to the number of microorganisms with which an object iscontaminated. The degree of sterilization is typically measured by asterility assurance level (SAL) which refers to the probability of aviable microorganism being present on a product unit aftersterilization. The required SAL for a product is dependent on theintended use of the product. For example, a product to be used in thebody's fluid path is considered a Class III device. SAL's for variousmedical devices can be found in materials from the Association for theAdvancement of Medical Instrumentation (AAMI) in Arlington, Va.

Radiation sterilization is well known to those of ordinary skill theart. Medical articles composed in whole or in part of polymers can besterilized by various types of radiation, including, but not limited to,electron beam (e-beam), gamma ray, ultraviolet, infra-red, ion beam,x-ray, and laser sterilization. A sterilization dose can be determinedby selecting a dose that provides a required SAL. A sample can beexposed to the required dose in one or multiple passes.

However, it is known that radiation can degrade the properties of thepolymers and drugs being exposed to the radiation. In particular, theradiation can induce chemical radiation of the polymer and drug.High-energy radiation such as e-beam and gamma radiation tends toproduce ionization and excitation in polymer molecules. Theseenergy-rich species undergo dissociation, subtraction, and additionreactions in a sequence leading to chemical stability. The stabilizationprocess can occur during, immediately after, or even days, weeks, ormonths after irradiation which often results in physical and chemicalcross-linking or chain scission. Chain scission can result in areduction in molecular weight. Resultant physical changes can includeembrittlement, discoloration, odor generation, stiffening, andsoftening, among others.

In particular, the deterioration of the performance of polymericmaterials and drugs due to e-beam radiation sterilization has beenassociated with free radical formation in polymer-containing portions ofdevices exposed to e-beam radiation. “Free radicals” refer to atomic ormolecular species with unpaired electrons on an otherwise open shellconfiguration. Free radicals can be formed by oxidation reactions. Theseunpaired electrons are usually highly reactive, so radicals are likelyto take part in chemical reactions, including chain reactions. The freeradicals formed due to radiation exposure can react with the polymerchains of the polymer-containing portions resulting in degradation ofthe polymer. The reactions are dependent on e-beam dose and temperature.

Furthermore, the release rate of a drug in a polymer-containing portionof device can be adversely affected by the degradation of the polymer.In addition, drugs in the polymer-containing portions are also subjectto chemical degradation due to free radical formation induced byradiation exposure. Drugs can also chemically degrade due to increasedtemperatures induced by the e-beam radiation.

Stents and delivery systems are typically sterilized, packaged, stored,and transported in a “ready to implant” configuration in which the stentis disposed at the distal end of a catheter of a delivery system. Asheath can also be disposed over the stent to secure the stent to theballoon. Stents and stent delivery assemblies can additionally bestored, transported, as well as sterilized in flexible, sealed storagecontainers, such as a foil pouch, that protects the stent and assemblyfrom damage and environmental exposure (humidity, oxygen, light, etc.)which can have an adverse effect on the stent and delivery system. Suchcontainers can be in the form of a pouch or sleeve. For example, thecontainer can be constructed of two sheets or lamina which have beenjoined along an edge. Also, the container can be constructed of a singlesheet or lamina which has been folded and sealed along all edges oralong all non-folded edges; or a bag or pocket which is sealed along oneor more edges. The pouches can be made from a polymer, glass, ceramic,metallic substance, or a combination thereof. A pouch containing a stentand delivery system can be further disposed within a rigid container toprotect the pouch and the stent and delivery system contained therein.The rigid container can be, for example, a box, such as a chipboard box.

A system for sterilizing a packaged stent delivery assembly includes aradiation source, such as an e-beam source, and a fixture for supportingthe package. The support fixture is moved, for example, on a conveyerarrangement past an e-beam source in a manner that an e-beam is directedonto the stent delivery system assembly. FIG. 3 depicts a schematicillustration of a fixture 300 that supports a package 305 containing astent 310 disposed on a stent-delivery assembly 315. Fixture 300includes a bottom support 325 and a back support arm 330. A radiationsource 335 directs radiation as shown by an arrow 340. Fixture 300 canbe moved by a conveyer system (not shown) as shown by an arrow 345 pastradiation source 335 to sterilize the stent-delivery system assembly incontainer 305.

Various embodiments of the present invention include stents and stentdelivery assemblies that have a substance in or on polymer-containingportions that reduce or prevent chemical degradation induced byradiation used to sterilize the stents and stent delivery assemblies.Such substances can also reduce or prevent chemical degradation of drugswithin polymer-containing portions of stents. In such embodiments, thesubstance can be incorporated within or on a polymer-containing portionsuch as a stent or stent delivery assembly.

As noted above, e-beam radiation exposure to a polymer can lead to freeradical formation within the polymer. In certain embodiments, thesubstance for reducing or preventing chemical degradation can be a freeradical scavenger or antioxidant. “Free radical scavengers” or“antioxidants” are molecules that slow or prevent the oxidation of otherchemicals. Free radical scavengers or antioxidants can remove freeradical intermediates that can participate in chain reactions, thusterminating such reactions. Free radical scavengers or antioxidants canalso inhibit other oxidation reactions by being oxidized themselves. Incertain embodiments of the present invention, free radical scavengers orantioxidants remove free radicals that can cause chain reactions thatresult in chemical degradation of a polymer-containing portion of astent or stent delivery assembly.

As shown in FIG. 1, a stent can include a substrate or scaffolding thatis designed to support the walls of a body lumen. In some embodiments,the stent substrate can be formed from a polymer, such as abioabsorbable polymer. A substance such as a free radical scavenger orantioxidant that reduces or prevents chemical degradation due toradiation exposure can be mixed or dispersed within the polymer. Thesubstance can reduce or prevent chemical degradation to a degree thatcauses degradation of mechanical properties of the substrate. Suchmechanical properties can be strength, toughness, and stiffness. A stentsubstrate can include 0.001-5 wt %, 0.01-2 wt %, or more narrowly,0.01-1 wt % of a free radical scavenger or antioxidant.

As noted above, a polymer stent substrate can be fabricated from apolymer tube. Polymer constructs such as tubes can be formed byextrusion. Prior to extrusion, the chemical degradation-reducingsubstance can be incorporated into a polymer through solution blending,melt blending, or a combination thereof. In some embodiments, thesubstance may be part of the polymer molecule, i.e., covalently bondedto the polymer rather than mixed.

The polymer with the substance can then be extruded to form a tube.Alternatively or additionally, the substance can be mixed or compoundedwith the polymer during extrusion. A laser can then be used to cut apattern in the tube.

In further embodiments, a stent with either a metal or polymer substratecan include a polymer-containing coating that includes a chemicaldegradation-reducing substance such as a free radical scavenger orantioxidant. A stent coating can include various types of coating layersincluding, but not limited to, a drug-polymer layer, a primer layer, anda topcoat layer. FIG. 4 depicts a close-up schematic view of a stentsurface showing a stent substrate 400. Substrate 400 includes a coatingwith a primer layer 405, a drug-polymer layer 410, and a topcoat layer415. Drug-polymer layer 405 includes an active agent or drug 420dispersed within a polymer carrier 425.

A primer layer is typically disposed between a stent substrate and adrug-polymer layer to facilitate adhesion between the substrate and thedrug-polymer layer. The topcoat layer is a polymer typically disposedabove a drug-polymer layer to control the rate of delivery of the druginto the body from the drug-polymer layer. A coating layer can include0.001-10 wt %, 0.01-5 wt %, 0.01-2 wt %, or more narrowly, 0.01-1 wt %of a free radical scavenger or antioxidant.

Various embodiments can include incorporating the chemicaldegradation-reducing substance in one or more of the layers of thecoating. The various layers and the substrate can have the samesubstance and the same concentration by weight or volume in each layer.Alternatively, the layers may have different concentrations of thesubstance, depending on the desired or required protection from chemicaldegradation caused by radiation. For example, a drug-polymer layer mayhave a higher concentration of the substance than other layers or thanthe stent substrate. Additionally, in some embodiments, at least onelayer may have a different type of free radical scavenger or antioxidantthan other layers. The type of free radical scavenger or antioxidant canbe selected based on desired protection from chemical degradation.

The type and amount of free radical scavenger selected for a layer canbe selected based on a desired or necessary protection from chemicaldegradation. For instance, it is important for each of the layers tohave sufficient toughness and flexibility to resist cracking anddelamination. In particular, a primer layer can include sufficientamount of the substance to reduce or prevent chemical degradation thatcould reduce the adhesion of the primer layer to the substrate. Inaddition, the drug-polymer layer can include a substance to reduce orprevent chemical degradation of the polymer carrier for the drug and thedrug within the polymer carrier. The drug-polymer layer can include asufficient amount of the substance to reduce or prevent radiation fromdegrading the drug and modifying the mechanical properties and the drugelution properties of the carrier polymer. Additionally, the topcoatlayer can include a sufficient amount of the substance to preventradiation from significantly modifying the mechanical properties and thedrug elution properties of the topcoat layer polymer.

Additionally, the type of free radical scavenger or antioxidant can beselected based on the type of polymer of the stent substrate or coatinglayer. Only specific types of free radical scavengers or antioxidantsmay be capable of reducing or preventing chemical degradation in aspecific polymer.

The incorporated free radical scavengers and antioxidants may bereleased through diffusion or material degradation during delivery andafter implantation. Additionally, a free radical scavenger orantioxidant can be selected based on its therapeutic affect uponimplantation. In addition to reducing chemical degradation, the presenceof free radical scavengers or antioxidants in a polymer stent substrateor within a polymer coating can have a therapeutic benefit when they arereleased into the body. For example, it has been demonstrated thatVitamin E can protect against atherosclerosis in both animals andhumans. A. C. Chan, The Journal of Nutrition, Vol. 128, No. 10, October1998, pp. 1593-1596.

In further embodiments, a polymer-containing portion of a stent deliveryassembly can include a substance that reduces or prevents chemicaldegradation in the polymeric portion arising from exposure to radiationduring sterilization. Various polymer-containing portions of astent-delivery assembly can include such a substance, including, but notlimited to a catheter, balloon, or restraining sheath. In someembodiments, the substance can be mixed or dispersed within thepolymer-containing portion, such as within the body of the catheter,balloon, or restraining sheath.

Polymer containing portions can be fabricated using extrusion, injectionmolding, compression molding, rotational molding, dip coating,electrospinning, etc among the many processing possibilities. Thesubstance can be incorporated into a polymer by solution blending, meltblending, imbibing, or a combination thereof. The polymer with thesubstance can then be processed by extrusion, injection molding, orother process to form a catheter, balloon, or sheath. Alternatively, thesubstance can be mixed with the polymer during extrusion or injectionmolding or the selected processing technique.

Various free radical scavengers and antioxidants, both synthetic ornatural, may be used to reduce or prevent chemical degradation inpolymer-containing portions of a stent or stent delivery assembly.Representative examples of free radical scavengers or antioxidants thatcan be to reduce or eliminate chemical degradation due to radiationinclude, L-ascorbate (Vitamin C), Vitamin E, herbal rosemary, sageextracts, glutathione, melatonin, carotenes, resveratrol, butylatedhydroxyanisole, butylated hydroxytoluene, propyl gallate,tertbutylhydroquinone, and combinations thereof. Various isomers ofVitamin E may be used, including the four tocopherols and fourtocotrienols. The alpha, beta, gamma and delta forms of both thetocopherols and tocotrienols may be used to prevent chemicaldegradation. In particular, butylated hydroxytoluene can be used indrug-polymer layers to reduce or prevent degradation of active agents.

Low molecular weight free radical scavengers or antioxidants may besusceptible to leaching from polymer materials. Thus, such free radicalscavengers or antioxidants may at least partially leach out of apolymer-containing portion of a stent or delivery assembly prior toradiation sterilization. Oligomeric or polymeric free radical scavengersor antioxidants are less susceptible to leaching from a polymermaterial. Thus, some embodiments can include using oligomeric orpolymeric free radical scavengers or antioxidants in polymer-containingportions of a stent or delivery assembly. Representative examples ofoligomeric or polymeric free radical scavengers or antioxidants include,but are not limited to, oligomeric or polymeric proanthocyanidins,polyphenols, polyphosphates, polyazomethine, high sulfate agaroligomers, chitooligosaccharides obtained by partial chitosanhydrolysis, polyfunctional oligomeric thioethers with stericallyhindered phenols. Some polymeric free radical scavengers can be bondedor grafted on the backbone of a polymer to be protected and blended withadditional polymer. The blend can then be used to fabricate a stent,coating, or part of a stent delivery system.

In further embodiments, a stent and stent delivery system that includesa free radical scavenger or antioxidant can be radiation sterilized in avacuum or near vacuum environment. Ambient oxygen and oxygen dissolvedin a polymer-containing portion of a stent or delivery assembly canfacilitate chemical degradation induced by radiation. Thus, reducing oreliminating ambient and dissolved oxygen can further reduce suchchemical degradation. In such embodiments, a pouch containing the stentand delivery assembly can be evacuated of air or other gas and sealed. Apouch can be evacuated using vacuum packaging or sealing equipment thatare known to those of skill in the art of vacuum packaging.

In further embodiments, a stent and stent delivery system that includesa free radical scavenger or antioxidant can be radiation sterilized inan oxygen-free environment or gas. An oxygen free environment caninclude gases such as argon, nitrogen, or helium. After evacuating apouch containing a stent and delivery system, the pouch can be filledwith an oxygen free gas. “Oxygen-free” gas can refer to a gas that thatincludes no or substantially no oxygen. “Substantially no oxygen” canrefer to a gas having less than 1%, 0.05%, or less than 0.01% oxygen.

Therefore, the modification of polymer properties due to radiation isgenerally due the reactions which are chemical in nature as well as theincrease in temperature of a sample. Thus, it is believed that reducingthe temperature of a polymer-containing device before, during, and aftersterilization can slow down the rate of that the modification occurswhich can reduce or eliminate adverse affects of radiationsterilization.

Furthermore, it is believed that the rate of at least some of thechemical degradation reactions induced by radiation decrease withtemperature. In additional embodiments, a stent and delivery system canbe radiation sterilized at a sterilization temperature (Ts) which isbelow an ambient temperature. Ambient temperature can refer to atemperature between about 15-30° C. In such embodiments, a stent anddelivery system can be cooled to a Ts and then radiation sterilized. TheTs can be, for example, less than ambient temperature of the polymer. Invarious embodiments, Ts can be less than 10° C., 0° C., −15° C., −25°C., −40° C., −70° C., −100° C., −150° C., −200° C., −240° C., or lessthan −270° C. The stent and delivery system can be cooled to a Ts byvarious methods, such as, for example, by disposing the stent anddelivery system in a freezer for a duration sufficient to cool the stentand delivery system to Ts. In additional embodiments, post-sterilizationprocessing can be performed using a temperature cycle to quench oreliminate trapped radicals that were formed during the radiationsterilization process.

The underlying structure or substrate of a stent can be completely or atleast in part made from a biodegradable polymer or combination ofbiodegradable polymers, a biostable polymer or combination of biostablepolymers, or a combination of biodegradable and biostable polymers.Additionally, a polymer-based coating for a surface of a device can be abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers.

A polymer for use in fabricating an implantable medical device, such asa stent, can be biostable, bioabsorbable, biodegradable, biosoluble orbioerodable. Biostable refers to polymers that are not biodegradable.The terms biodegradable, bioabsorbable, and bioerodable are usedinterchangeably and refer to polymers that are capable of beingcompletely degraded and/or eroded when exposed to bodily fluids such asblood and can be gradually resorbed, absorbed and/or eliminated by thebody. The processes of breaking down and absorption of the polymer canbe caused by, for example, hydrolysis and metabolic processes.Biosoluble polymers clear the body by dissolution followed byelimination.

It is understood that after the process of degradation, erosion,absorption, and/or resorption has been completed, no part of the stentwill remain or in the case of coating applications on a biostablescaffolding, no polymer will remain on the device. In some embodiments,very negligible traces or residue may be left behind. For stents madefrom a biodegradable polymer, the stent is intended to remain in thebody for a duration of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished.

Representative examples of polymers that may be used to fabricate asubstrate of an implantable medical device or a coating for animplantable medical device include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(L-lactide-co-glycolide);poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate),polyethylene amide, polyethylene acrylate, poly(glycolicacid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers other than polyacrylates,vinyl halide polymers and copolymers (such as polyvinyl chloride),polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidenehalides (such as polyvinylidene chloride), polyacrylonitrile, polyvinylketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters(such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABSresins, polyamides (such as Nylon 66 and polycaprolactam),polycarbonates, polyoxymethylenes, polyimides, polyethers,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose.

Additional representative examples of polymers that may be especiallywell suited for use in fabricating an implantable medical devicedisclosed herein include ethylene vinyl alcohol copolymer (commonlyknown by the generic name EVOH or by the trade name EVAL™), poly(butylmethacrylate), poly(vinylidene fluoride-co-hexafluororpropene) (e.g.,SOLEF® 21508, available from Solvay Solexis PVDF, Thorofare, N.J.),polyvinylidene fluoride (otherwise known as KYNAR®, available fromAtofina Chemicals, Philadelphia, Pa.), ethylene-vinyl acetatecopolymers, and polyethylene glycol.

A non-polymer substrate of an implantable medical device, such as astent, may be made of a metallic material or an alloy such as, but notlimited to, cobalt chromium alloy (ELGILOY®), stainless steel (316L),high nitrogen stainless steel, e.g., BIODUR® 108, cobalt chrome alloyL-605, “MP35N,” “MP20N,” ELASTINITE® (Nitinol), tantalum,nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, orcombinations thereof. “MP35N” and “MP20N” are trade names for alloys ofcobalt, nickel, chromium and molybdenum available from Standard PressSteel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Additionally, a coating for animplantable medical device can be composed of a non-polymer material.Non-polymer coatings include, but are not limited to, microporouscarbon, metal, and ceramic.

A drug or active agent can include, but is not limited to, any substancecapable of exerting a therapeutic, prophylactic, or diagnostic effect.The drugs for use in the implantable medical device, such as a stent ornon-load bearing scaffolding structure may be of any or a combination ofa therapeutic, prophylactic, or diagnostic agent. Examples of activeagents include antiproliferative substances such as actinomycin D, orderivatives and analogs thereof. (manufactured by Sigma-Aldrich 1001West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN™ availablefrom Merck). Synonyms of actinomycin D include dactinomycin, actinomycinIV, actinomycin I₁, actinomycin X₁, and actinomycin C₁. The bioactiveagent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel, (e.g., TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.),docetaxel (e.g., Taxotere®, from Aventis S.A., Frankfurt, Germany),methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g., Adriamycin® from Pharmacia & Upjohn,Peapack N.J.), and mitomycin (e.g., Mutamycin® from Bristol-Myers SquibbCo., Stamford, Conn.). Examples of such antiplatelets, anticoagulants,antifibrin, and antithrombins include aspirin, sodium heparin, lowmolecular weight heparins, heparinoids, hirudin, argatroban, forskolin,vapiprost, prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, and thrombin inhibitors such as Angiomax™ (Biogen,Inc., Cambridge, Mass.). Examples of such cytostatic orantiproliferative agents include angiopeptin, angiotensin convertingenzyme inhibitors such as captopril (e.g., Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g., Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.), calcium channel blockers (such as nifedipine),colchicine, proteins, peptides, fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate agents include cisplatin,insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin,alpha-interferon, genetically engineered epithelial cells, steroidalanti-inflammatory agents, non-steroidal anti-inflammatory agents,antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, estradiol, antibiotics, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, ABT-578, clobetasol, cytostatic agents,prodrugs thereof, co-drugs thereof, and a combination thereof. Othertherapeutic substances or agents may include rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the name of everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, methyl rapamycin, and40-O-tetrazole-rapamycin.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects.

1. A stent comprising: a polymeric portion; optionally, a drug; and a chemical degradation-reducing substance that reduces or prevents chemical degradation of a polymer of the polymeric portion and/or the optional drug, the chemical degradation arising from exposure to radiation during sterilization; wherein the substance comprises a polymeric or oligomeric free radical scavenger or antioxidant selected from the group consisting of chitooligosaccharides obtained by partial chitosan hydrolysis.
 2. The stent of claim 1, wherein the radiation comprises e-beam or gamma radiation.
 3. The stent of claim 1, the polymeric portion comprises a biostable or bioabsorbable polymer, the substance being dispersed within the polymeric portion.
 4. The stent of claim 1, wherein substance further comprises a free radical scavenger or antioxidant selected from the group consisting of L-ascorbate, Vitamin E, herbal rosemary, sage extracts, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tertbutylhydroquinone, and combinations thereof.
 5. The stent of claim 1, wherein the polymeric portion is at least a part of a coating on the stent.
 6. The stent of claim 5, wherein the substance is dispersed within the polymeric portion.
 7. The stent of claim 1, wherein the polymeric portion is at least a part of a material from which the stent is formed.
 8. The stent of claim 7, wherein the substance is dispersed within the polymeric portion.
 9. A stent comprising: a polymeric portion; optionally, a drug; and a chemical degradation-reducing substance that reduces or prevents chemical degradation of a polymer of the polymeric portion and/or the optional drug, the chemical degradation arising from exposure to radiation during sterilization; wherein the substance comprises a polymeric or oligomeric antioxidant or free radical scavenger selected from the group consisting of polyazomethine, high sulfate agar oligomers, and combinations thereof.
 10. The stent of claim 9, wherein the radiation comprises e-beam or gamma radiation.
 11. The stent of claim 9, wherein the polymeric portion comprises a biostable or bioabsorbable polymer, the substance being dispersed within the polymeric portion.
 12. The stent of claim 9, wherein the polymeric portion is at least a part of a material from which the stent is formed, and wherein the substance is dispersed within the polymeric portion.
 13. The stent of claim 9, wherein the stent comprises a metallic material or an alloy.
 14. The stent of claim 9, wherein the polymeric portion is at least a part of a coating on the stent, and the substance is dispersed within the polymeric portion.
 15. The stent of claim 14, wherein the polymeric portion is a substance layer of the coating, the substance being dispersed within the substance layer of the coating, and the substance layer being disposed above and/or below a layer of the coating comprising the drug and a polymer.
 16. The stent of claim 9, wherein substance further comprises a free radical scavenger or antioxidant selected from the group consisting of L-ascorbate, Vitamin E, herbal rosemary, sage extracts, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tertbutylhydroquinone, and combinations thereof.
 17. The stent of claim 9, wherein the substance comprises polyazomethine.
 18. The stent of claim 9, wherein some of the polymeric or oligomeric antioxidant or free radical scavenger are bonded or grafted to a polymer of the polymeric portion which may be the polymer of the polymeric portion for which chemical degradation is reduced by the substance, or a different polymer.
 19. A stent delivery assembly optionally comprising a drug, and comprising a polymeric portion, the polymeric portion comprising a chemical degradation-reducing substance that reduces or prevents chemical degradation of a polymer of the polymeric portion and/or the optional drug, the chemical degradation arising from exposure to radiation during sterilization; wherein the substance comprises a polymeric or oligomeric free radical scavenger or antioxidant selected from the group consisting of polyazomethine, high sulfate agar oligomers, and combinations thereof.
 20. The assembly of claim 19, wherein the radiation comprises e-beam or gamma radiation.
 21. The assembly of claim 19, wherein the polymeric portion comprises a catheter, the substance being dispersed within a polymer of the catheter which may be the polymer of the polymeric portion for which chemical degradation is reduced by the substance, or a different polymer.
 22. The assembly of claim 19, wherein the polymeric portion comprises a coating above a catheter, stent delivery balloon, or restraining sheath disposed over a stent disposed over a catheter, the coating including the substance dispersed within the coating.
 23. The assembly of claim 19, wherein the polymeric portion comprises a restraining sheath disposed over a stent, the substance being dispersed within a polymer of the restraining sheath which may be the polymer of the polymeric portion for which chemical degradation is reduced by the substance, or a different polymer.
 24. The assembly of claim 19, wherein the polymeric portion comprises a balloon, the substance being dispersed within a polymer of the balloon which may be the polymer of the polymeric portion for which chemical degradation is reduced by the substance, or a different polymer.
 25. The assembly of claim 19, wherein the chemical degradation comprises reactions of free radicals with the polymer of the polymeric portion, the substance reducing or preventing the reactions.
 26. The assembly of claim 19, wherein the substance further comprises a free radical scavenger or antioxidant selected from the group consisting of L-ascorbate, Vitamin E, herbal rosemary, sage extracts, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tertbutylhydroquinone, and combinations thereof.
 27. The assembly of claim 19, wherein the substance comprises polyazomethine.
 28. The assembly of claim 19, wherein some of the polymeric or oligomeric antioxidant or free radical scavenger are bonded or grafted to a polymer of the polymeric portion, which may be the polymer of the polymeric portion for which chemical degradation is reduced by the substance, or a different polymer. 